Nucleoside analogues that are potent inhibitors of purine nucleoside phosphorylase (PNP) and purine phosphoribosyltransferases (PPRT) are useful in treating parasitic infections, T-cell malignancies, autoimmune diseases and inflammatory disorders {see e.g. V. L. Schramm, Biochimica et Biophysica Acta, 1587 (2002) 107-117}. The analogues are also useful for immunosupression in organ transplantation.
Related nucleoside analogues that are potent inhibitors of 5′-methylthioadenosine phosphorylase (MTAP) and 5′-methylthioadenosine nucleosidase (MTAN) are useful:    (a) as anti-microbial compounds, and in decreasing the virulence of microbial infections by decreasing production of the quorum sensing pathway;    (b) as agents for treating parasitic infections such as malaria that infects red blood cells {see e.g. G. A. Kicska et al., J. Biol. Chem., 277 (2002) 3226-3231}; and    (c) as anti-tumour compounds, potentially in combination therapy with methotrexate or azaserine.
The applicants have previously disclosed potent inhibitors of such enzymes in a class called the Immucillins, based upon deazapurines covalently linked directly to aza-sugar moieties (U.S. Pat. Nos. 5,985,848 and 6,066,722, “Inhibitors of Nucleoside Metabolism”; and WO 02/19371, “Nucleoside Metabolism Inhibitors”).
In the search for new and improved nucleoside analogues that are potent inhibitors of the aforementioned nucleoside phosphorylases and nucleosidases, the applicants have also discovered a new class of compounds that are potent inhibitors of these nucleoside phosphorylases and hydrolases (PCT Patent Application PCT/NZ03/00186, “Inhibitors of Nucleoside Phosphorylases and Nucleosidases”).
The preparation of such nucleoside analogues is by way of multi-step chemical syntheses. Consequently, the time and cost required for each synthesis can be considerable. There is therefore a need for more efficient and cost effective methods of preparing compounds in this new class.
The Mannich reaction is a condensation reaction between three components, namely an amine, formaldehyde and a compound with an active hydrogen atom such as a heteroaromatic compound e.g. indole (pages 812-814, Vogel's Textbook of Practical Organic Chemistry, 4th Edition, revised by B. S. Fumiss, A. J. Hannaford, V. Rogers, P. W. G. Smith and A. R. Tatchell, Longmans, London, 1978).
Mannich reactions have been used to assemble compounds that incorporate a 9-deazapurine moiety linked via a methylene group to aliphatic and alicyclic amines [G. A. Modnikova et al., “Pyrrolo[3,2-d]pyrimidines. III. 7-Aminomethyl-substituted pyrrolo[3,2-d]pyrimidines”, Khim.-farm. Zh., 1983, 352-356 (English translation)]. Compounds that incorporate a pyrimidine moiety linked via a methylene group to a cyclic secondary amine have also been assembled using Mannich reactions. [V. V. Filichev and E. B. Pedersen, “Synthesis of 1′-aza-C-nucleosides from (3R,4R)-4-(hydroxymethyl)pyrrolidin-3-ol”, Tetrahedron, 57 (2001) 9163-9168].
The applicants have now found that a Mannich reaction can be used to prepare compounds that incorporate a 9-deazapurine or an 8-aza-9-deazapurine moiety (or their 2-aza-analogues) linked via a methylene group to a cyclic secondary amine. These compounds are described as potent inhibitors, or potentially potent inhibitors, of nucleoside phosphorylases and nucleosidases in PCT Patent Application PCT/NZ03/00186.
It is therefore an object of the present invention to provide a process for preparing these compounds, or at least to provide a useful choice.